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Why do we need new drugs in PV and ET?. BCSH Guidelines: Hydroxycarbamide 1st Line PV ET.

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Presentation on theme: "Why do we need new drugs in PV and ET?. BCSH Guidelines: Hydroxycarbamide 1st Line PV ET."— Presentation transcript:

1 Why do we need new drugs in PV and ET?

2 BCSH Guidelines: Hydroxycarbamide 1st Line PV ET

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5 Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: – Failure to normalise blood counts – Fails to normalise vascular risks – Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

6 Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: – Failure to normalise blood counts – Fails to normalise vascular risks – Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

7 Symptomatic burden prevalent across all MPN Mesa R. et. al. Cancer 2007;109:68-76

8 Systemic symptoms: pruritus Among 1,953 PV patients from 10 studies, 42% (31%-69%) reported pruritus Reportedly associated with significant impairment of QoL in 19/44 (43%) of the patients in one study Agent JAK2 inhibitors mTOR inhibitor HDAC inhibitors Interferon Paroxetine/Fluoxetine H1-H2 blockers Anti-allergic Myelosuppression Phlebotomy Efficacy Saini KS et al., Eur J Clin Inv 2010; 40:828-34

9 Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: – Failure to normalise blood counts – Fails to normalise vascular risks – Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

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15 Resistance in 11%; Intolerance 13%

16 Limitations of Hydroxycarbamide in PV and ET Poor control of symptoms Resistance: – Failure to normalise blood counts – Fails to normalise vascular risks – Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

17 Am J Hematology, of 3411 (5%) developed side effects 167 mucocutaneous 16 fever 1 pneumonitis

18 Intolerance to HU 3,411 MPN pts 1 Side Effects 184 pts (5%) * Fever 16 pts (8.5%) Pneumonitis 1 pt No Side Effect 2,831 pts Mucosal/cutaneous 167 pts (91%) 1 Antonioli E et al., Am J Hematol 2012, In press; 2 Harrison c et al, NEJM 2005; 353:33-45; 3 Hernandez-Boluda JC et al, BJH 2010; 152:81-8 * 11% in PT % in 3

19 Limitations of Hydroxycarbamide in PV and ET Paucity of randomised trials in PV Poor control of symptoms Resistance: – Failure to normalise blood counts – Fails to normalise vascular risks – Persistent splenomegaly Side effects Leukaemogenicity? Lack of disease modifying effect Lack of ability to reduce late myeloid transformation

20 Risk factors for transformation in PV Marchioli et al, JCO, 2005

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22 Choice of second line treatments Relax treatment targets Erythropoietin to help control anaemia in selected patients Anagrelide Interferon – standard – pegylated Alkylating agents P32 Investigatory agents Combination treatment Transplant Very little prospective trial data on which to base decisions Use non leukaemogenic agents where possible

23 Cortelazzo, 1995

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25 Interferon: Non-leukaemogenic

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29 Forthcoming MPD RC PEGASYS studies Phase JAK2V617F +ve ET/PV patients HU resistant/refractory and 20 patients with splanchnic vein thrombosis Phase JAK2V617F +ve ET/PV patients diagnosed within 3 years of trial entry Randomised between PEGASYS + aspirin and HU + aspirin

30 Current status of experimental therapies HDAC inhibitors – panobinostat, givinostat, vorinostat HDAC inhibitors – panobinostat, givinostat, vorinostat JAK 2 inhibitors JAK 2 inhibitors

31 Durable Responses with the JAK1/JAK2 Inhibitor, INCB018424, in Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU) Srdan Verstovsek 1, Francesco Passamonti 2, Alessandro Rambaldi 3, Giovanni Barosi 4, Peter Rosen 5, Richard Levy 6, Edward Bradley 6, William Garrett 6, Kris Vaddi 6, Nancy Contel 6, Victor Sandor 6, Reid Huber 6, Lee Schacter 7, Elisa Rumi 2, Elisabetta Gattoni 4, Elisabetta Antonioli 8, Lisa Pieri 8, Mario Cazzola 2, Hagop Kantarjian 1, Tiziano Barbui 3, Alessandro M. Vannucchi Annual Meeting of the American Society of Hematology December 6, Department of Leukemia, University of Texas MD Anderson Cancer Research Center, Houston,Tx, 2 Division of Hematology, University of Pavia, Fondazione Istituto di Ricovero e Cura a Carattere, Scientifico Policlinico San Matteo, Pavia, Italy, 3 Division of Hematology, Ospedali Riuniti, Bergamo, Italy, 4 Unit of Clinical Epidemiology and Center for the Study of Myelofibrosis, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy, 5 Tower Cancer Research Foundation, Beverly Hills, Ca, 6 Incyte Corporation, Wilmington, De, 7 Pfizer Corporation, New York,, 8 Section of Hematology, Deparment of Critical Care, University of Florence, Italy

32 Essential Thrombocythemia (N=39) Polycythemia vera (N=34) 25 mg BID (n=8) 50 mg QD (n=8) 10 mg BID (n=8) 25 mg BID (n=15) (n=8) 50 mg QD (n=7) 10 mg BID (n=7) (n=12) Part 1Part 2 Part 1Part 2 Phase II Study of INC424 in Patients with Advanced ET and PV Eligibility Criteria: Refractory or intolerant to hydroxyurea (HU) or HU contraindicated PV: Hct > 45% OR phlebotomy 2 times in last 6 months, with at least one phlebotomy in last 3 months ET: Platelets > 650 x 10 9 /L unless on therapy Srdan Verstovsek et at ASH, December 6, 2010

33 PV Results: Splenomegaly and WBC 80% of patients with palpable splenomegaly (n=25) achieved ≥ 50% reduction as of the last follow-up (68% achieved complete resolution of palpable splenomegaly) Leukocytosis (>15x10 9 /L) was present in 15 patients at baseline: 73% normalized WBC as of the last follow-up visit Srdan Verstovsek et at ASH, December 6, 2010

34 PV Results: Platelet Counts and symptoms Thrombocytosis (>600 x10 9 /L) was present in 13 patients at baseline: platelets normalized in 69% as of the last follow-up visit Night Sweats Bone Pain Pruritus Mean Symptom Severity Scores Srdan Verstovsek et at ASH, December 6, 2010

35 PV Response  Response Criteria - European LeukemiaNet 1 – CR: Hct < 45% without phlebotomy, platelet count < 400,000, WBC < 10,000, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances) – PR: Hct 3 of the other criteria  97% overall response – 50% CR – 47% PR (spleen measured by palpation) 1 Barosi et al., Blood 113: , 2009

36 PV – ASH 2012 update 97% OR; 79% OR at 48 weeks, maintained in 74% at week 144

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40 Platelet Count Reduction in ET  49% achieved normal platelet counts and 79% achieved <600,000 or a ≥50% reduction as of last follow-up visit  13 of 14 subjects with baseline platelet counts >1,000,000 have achieved a greater than 50% reduction

41 ET Response  Response Criteria - European LeukemiaNet 1 – CR: Platelet count < 400 x10 9 /L, WBC < 10 x10 9 /L, normal spleen, no disease-related symptoms (pruritus, headache, microvascular disturbances) – PR: Platelet count 50% from baseline  90% overall response – 26% CR – 64% PR 1 Barosi et al., Blood 113: , 2009

42 MAJ C A RandoMised study of best Available therapy versus JAK Inhibition in patients with high risk Polycythaemia Vera or Essential Thrombocythaemia who are resistant or intolerant to HydroxyCarbamide TAP

43 Trial Schema 1:1 Randomisation PV: N = 90 patients per arm. ET: N = 55 patients per arm Patients stratified by disease type Ruxolitinib PV patients - 10 mg twice daily ET patients – 25mg twice daily Commence within 1 week of randomisation Best Available Therapy Commence within 1 week of randomisation BAT - any active agent but not solely venesection or supportive care Complete or Partial Response Continue Ruxolitinb and Follow-up for 5 years total FU minimum 2 monthly No response observed at 1 Year Continue Follow-up for 5 years Frequency at Investigators discretion Screening Patients with Polycythaemia vera or Essential Thrombocythaemia who are resistant to or intolerant of hydroxycarbamide Response assessed by European LeukemiaNet criteria within 1 year Change therapy

44 Summary Hydroxycarbamide is a well established and highly effective first line treatment for patients with ET and PV Patients who “fail” hydroxyurea treatment are at high risk of disease related complications Second line therapies are suboptimal and there is an unmet need for new agents for these hydroxycarbamide resistant patients Experimental therapy with JAK2i, pegylated interferon or HDACi show promise in these patients

45 Questions?


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